Liquid Formulations of Salts of 1-[2-(2,4-Dimethylphenylsulfanyl)Phenyl]-Piperazine

ABSTRACT

Liquid formulations of lactic acid addition salts of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine are provided.

CROSS REFERENCE TO PRIOR APPLICATIONS

This is a continuation of U.S. application Ser. No. 15/271,543, filedSep. 21, 2016, which is a continuation of U.S. application Ser. No.14/567,003, filed Dec. 11, 2014, which is a continuation of U.S.application Ser. No. 13/265,564, filed Nov. 1, 2011, now U.S. Pat. No.8,940,746, which is a U.S. National Phase application under 35 U.S.C. §371 of International Patent Application No. PCT/DK2010/050084, filedApr. 16, 2010, which in turn claims the priority of Danish PatentApplication No. PA200900531, filed Apr. 24, 2009 and U.S. ProvisionalApplication Ser. No. 61/214,540, filed Apr. 24, 2009, all of which areincorporated by reference herein. The International Applicationpublished in English on Oct. 28, 2010 as WO 2010/121621 under PCTArticle 21(2).

FIELD OF THE INVENTION

The present invention relates to liquid pharmaceutical formulations of1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.

BACKGROUND OF THE INVENTION

The compound 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine(compound I) has been disclosed in WO 03/029232 as the free base.Compound I has the molecular structure depicted below.

Different pharmaceutically acceptable acid addition salts of Compound Ihas been disclosed in WO 2007/144005, including the lactic acid additionsalt.

Compound I has been reported to exert serotonin transporter inhibition(WO 03/029232) and is said to be useful for the treatment of affectivedisorders, e.g. depression and anxiety. In addition, compound I exerts5-HT₃ antagonism and 5-HT_(1A) agonism which suggests this compound tobe useful e.g. in the treatment of cognitive impairment in depressedpatients, and the treatment of pain and residual symptoms in depression(WO 2007/144005 and WO 2008/113359).

In vitro and in vivo experiments conducted with compound I describingreceptor efficacy and disease pharmacology have been outlined in WO03/029232, WO 2007/144005 and WO 2008/113359.

Compound I has been tested in clinical trials in patients using HAM-D(Hamilton Rating Scale for Depression) as clinical end-point; fordetails see WO 2008/113359. The HAM-D scale may be used to assess theseverity of depression in patients by means of a 24 items questionnaire.According to the outcome of the clinical study compound I is believed tobe particularly useful in the treatment of depression avoiding sleep andsexual related adverse events (WO 2008/113359).

For many pharmaceutical compounds, oral administration of a tablet,capsule, pill or similar intended for swallowing is the preferredadministration form. However, some patients, e.g. elderly and pediatricpatients may have difficulties swallowing, and liquid solutions may be asuitable alternative avoiding the need for swallowing tablets, capsules,pills, etc. A liquid solution further provides a possibility of aflexible dosing regime. In order to limit the volume of a liquidsolution it is necessary to have a high concentration of the activeingredient in the solution, which again requires a high solubility ofthe active ingredient.

The present invention is related to liquid formulations of compound I.

SUMMARY OF THE INVENTION

The present inventors have surprisingly found that the L-lactic acidaddition salt (=L-lactate), the D-lactic acid addition salt (=D-lactate)and the DL-lactic acid addition salt (=DL-lactate) of1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine are highly soluble.Accordingly, the present invention relates to a liquid formulationcomprising the L-lactic acid addition salt, the D-lactic acid additionsalt and/or the DL-lactic acid addition salt of1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.

In one embodiment, the invention relates to a compound which is theL-lactic acid addition salt of1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.

In one embodiment, the invention relates to a compound which is theD-lactic acid addition salt of1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.

In one embodiment, the invention relates to a method of treatment, saidmethod comprising the administration of a liquid formulation of thepresent invention to a patient in need thereof.

In one embodiment, the invention relates to the use of a salt of thepresent invention in the manufacture of a liquid pharmaceuticalcomposition for the treatment of certain diseases.

In one embodiment, the invention relates to a salt of the presentinvention for use in the treatment of certain diseases, wherein saidsalts is in a liquid formulation.

In one embodiment, the present invention relates to a containercomprising a liquid formulation of the present invention, wherein saidcontainer is fitted with a drop aggregate.

FIGURES

FIG. 1: XRPD of L-lactate anhydrate 1 (AH1)

FIG. 2: XRPD of L-lactate monohydrate 1 (MH1)

FIG. 3: XRPD of L-lactate monohydrate 2 (MH2)

FIG. 4: XRPD of DL-lactate alpha form (α)

FIG. 5: XRPD of DL-lactate beta form (β)

FIG. 6: XRPD of DL-lactate monohydrate (MH), with content of α-form

FIG. 7: XRPD of DL-lactate gamma form (γ), with content of α-form

DETAILED DESCRIPTION OF THE INVENTION

The formulations to which the present invention relates are allpharmaceutical compositions.

Characterisation of the crystalline base and the previously known saltsof 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine has been describedin WO 2008/113359. The aqueous solubilities of these salts are shown inTable 2. Table 1 shows XRPD reflections, melting points and solubilitydata of salts of the present invention. As evidenced by the data fromTable 1 and 2, the DL-lactic acid addition salt β-form and the L-lacticacid addition salt MH2 have exceptionally high solubilities.Consequently, these salt forms would be suitable for application inliquid formulations comprising1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine. According to table2, also the mesylate salt benefits from extremely high solubility.However, use of methane sulfonic acid (mesylate) in combination withalcoholic solvents in the synthesis of pharmaceutical compositionsinvolves a risk of obtaining alkyl mesylate impurities which could begenotoxic (Mutat. Res. 581 (2005) 23-34; Eur. J. Pharm. Sci. 28 (2006)1-6). Lactate salts are accordingly superior to mesylate salts forapplication in pharmaceutical compositions.

For convenience, the L-lactic acid addition salt, the D-lactic acidaddition salt and the DL-lactic acid addition salt of1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine are referred to assalts of the present invention. Both the L-lactic acid addition salt andthe DL-lactic acid addition salt exist in several polymorphic forms asshown in the examples. Special mention is made of DL-lactic acidaddition salt β form as the salt of the present invention. For the sakeof convenience lactic acid addition salts are also referred to aslactates or lactate salts.

The polymorphic forms are characterized by their respective XRPDreflections listed in Table 1 and depicted in FIGS. 1-7.

In the present context the AH1 form of the L-lactate salt is intended toindicate an anhydrate form characterized by XRPD reflections at 4.65,10.96 and 13.97 (° 2θ), and further characterized by FIG. 1.

In the present context the MH1 form of the L-lactate salt is intended toindicate a first monohydrate form characterized by XRPD reflections at4.36, 8.73, 11.18, 11.81, 12.78 and 13.11 (° 2θ), and furthercharacterized by FIG. 2.

In the present context the MH2 form of the L-lactate salt is intended toindicate a second monohydrate form characterized by XRPD reflections at5.33, 9.75, 10.10, 14.44 and 14.63 (° 2θ), and further characterized byFIG. 3.

In the present context the α form of the DL-lactate salt is intended toindicate a first polymorph characterized by XRPD reflections at 6.67,8.33, 9.44, 11.82 and 15.35 (° 2θ), and further characterized by FIG. 4.

In the present context the β form of the DL-lactate salt is intended toindicate a second polymorph characterized by XRPD reflections at 6.01,10.10, 10.32, 12.06, 12.84, 13.08 and 13.58 (° 2θ), and furthercharacterized by FIG. 5.

In the present context the MH form of the DL-lactate salt is intended toindicate a monohydrate form characterized by XRPD reflections at 4.37,8.73, 11.14, 11.78, 12.75 and 13.11 (° 2θ), and further characterized byFIG. 6.

In the present context the γ form of the DL-lactate salt is intended toindicate a third polymorph characterized by XRPD reflections 4.63,10.94, 11.65 and 13.93 (° 2θ), and further characterized by FIG. 7.

Lactic acid is also known as 2-hydroxypropionic acid, and it forms an1:1 acid addition salt with1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine which is used in thepresent invention.

1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine may be prepared asdisclosed in WO 03/029232 and WO 2007/144005. The examples disclosespecific routes for obtaining the salts of the present invention. Inbrief, the L-lactate AH 1 and the DL-lactate α form may be prepared byaddition of L-lactic acid or DL-lactic acid, respectively, to1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine or vice versa in asuitable anhydrous organic solvent, such as ethyl acetate, followed byprecipitation, which precipitation may be brought about by e.g. cooling,removal of solvent, addition of another anhydrous solvent or acombination thereof.

The L-lactate MH1 is formed directly by exposure of L-lactate AH1 tohigher relative humidity. The L-lactate MH2 is the more stable form ofthe L-lactate monohydrates and is formed by adding 1 mL of water to 100mg of the L-lactate MH1. The aqueous solubility of the L-lactate MH2 is26 mg/mL. The DL-lactate β form is obtained from a slurry of theDL-lactate α form in water. The β form is the more stable polymorphicmodification of the DL-lactate and has a solubility of 8 mg/mL. TheDL-lactate MH is obtained by exposure of the DL-lactate α form to highrelative humidity. By heating the DL-lactate MH1 the DL-lactate γ formhas been obtained. Throughout this document (unless otherwise indicated)an indication of a concentration of a salt of the present invention,e.g. 5 mg/ml, is intended to indicate a concentration equivalent theindicated amount of free base, e.g. 5 mg/ml.

The inventors have noted that the presence of lactic acid informulations of the present invention increases the solubility of saltsof the present invention. The presence of lactic acid, either as D-, L-or DL-lactic acid, may increase the solubility of salts of the presentinvention to 20-25 mg/mL.

Only salts of L-lactic acid and DL-lactic acid have been made; however1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine is not chiral, andthe L-lactate and the D-lactate are enantiomers, and therefore theD-lactate exists (as mirror image) in the same crystal forms and havethe same XRPD-patterns, melting points and solubility as the L-lactate.X-ray powder difractograms (XRPD) for different forms of L-lactate saltand DL-lactate salt are depicted in FIG. 1-7.

Liquid formulations may be intended for oral or parenteraladministration. Liquid formulations for parenteral administrationincluding infusion solutions are in many aspects similar to other liquidformulations, but are additionally characterised by being sterile andisotonic.

The liquid oral formulation of the present invention may be presented asa syrup, an elixir, an oral solution, a suspension, or as a concentratedoral formulation. One advantage of these administration forms is thatthe patient does not have to swallow a solid form, which may bedifficult, in particular for elderly and pediatric patients or forpatients with traumas in the mouth or throat.

Syrups and elixirs are typically sweetened, flavoured liquids containingan active pharmaceutical ingredient. Syrups typically have higher sugarcontent, and elixirs often contain alcohol as well. An oral solution isa solution of the active ingredient. A suspension is a two-phase systemcomprising solid particles dispersed in a liquid. Administration ofsyrups, elixirs, oral solutions and suspensions typically involves theintake of relatively large amounts of liquid, i.e. 10-50 mL.

In contrast hereto, the concentrated oral formulations of the presentinvention are administered to the patient by measuring out apre-determined volume of said formulation from a suitable dispenser,adding the resulting volume to a glass of liquid (water, juice orsimilar) upon which the patient drinks the liquid. For convenience, thevolume measured out is small, e.g. less than 2 mL, such as less than 1mL, such as less than 0.5 mL. As an example of such product theregulatory authority in the UK, Medicines and Healthcare ProductsRegulatory Agency (MHRA), has approved a concentrated oral formulationcomprising the antidepressant citalopram at 40 mg/ml.

In a particular embodiment, a concentrated oral formulation of thepresent invention is administered to the patient by measuring out apre-determined number of drops of said formulation from a suitabledispenser, e.g. a container with a drop aggregate, adding the drops to aglass of liquid (water, juice or similar) upon which the patient drinksthe liquid. In this context, a drop aggregate is an aggregate fitted toa container that effects that a liquid inside said container may bedispensed from said container in discrete drops.

Preliminary results have indicated that the concentrated oralformulations of the present invention are prone to being unstable whenexposed to light. To overcome this potential problem the formulation canbe stored protected from light e.g. in an opaque container or in acontainer that is light protected by a box.

The concentration of a salt of the present invention in concentratedoral formulations is determined by the number of drops (or the volume)it is desired to collect and the amount of the salts it is desired toadminister. It is generally held that measuring out around 5-20 drops isan optimal compromise between safety/efficacy of the treatment on theone hand and convenience on the other. If the concentration of the saltsof the present invention is too high, i.e. if only a low number of dropsis to be measured out, it may jeopardize safety or efficacy of thetreatment. With a low number of drops, one or two drops more or lessthan desired will significantly increase the uncertainty in the doseprovided. On the other hand, if the concentration of the salts of thepresent invention is too low, the number of drops to be measured out ishigh, which is inconvenient for the patient or the caretaker.

With daily dosages of 2.5 mg, a concentrated oral formulation with aconcentration of 2.5 mg of active ingredient per mL could beappropriate. A concentration of 2.5 mg per mL and a drop number of 20drops/mL would make it possible to administer 20 drops for a dose of 2.5mg.

With daily dosages of 2.5 mg, a concentrated oral formulation with aconcentration of 5 mg of active ingredient per mL could be appropriate.A concentration of 5 mg per mL and a drop number of 20 drops/mL wouldmake it possible to administer 10 drops for a dose of 2.5 mg.

With daily dosages of 2.5 mg, a concentrated oral formulation with aconcentration of 10 mg of active ingredient per mL could be appropriate.A concentration of 10 mg per mL and a drop number of 20 drops/mL wouldmake it possible to administer 5 drops for a dose of 2.5 mg.

With daily dosages of 5 mg, a concentrated oral formulation with aconcentration of 5 mg of active ingredient per mL could be appropriate.A concentration of 5 mg per mL and a drop number of 20 drops/mL wouldmake it possible to administer 20 drops for a dose of 5 mg.

With daily dosages of 5 mg, a concentrated oral formulation with aconcentration of 10 mg of active ingredient per mL could be appropriate.A concentration of 10 mg per mL and a drop number of 20 drops/mL wouldmake it possible to administer 10 drops for a dose of 5 mg.

With daily dosages of 5 mg, a concentrated oral formulation with aconcentration of 20 mg of active ingredient per mL could be appropriate.A concentration of 20 mg per mL and a drop number of 20 drops/mL wouldmake it possible to administer 5 drops for a dose of 5 mg.

With daily dosages of 10 mg, a concentrated oral formulation with aconcentration of 10 mg of active ingredient per mL could be appropriate.A concentration of 10 mg per mL and a drop number of 20 drops/mL wouldmake it possible to administer 20 drops for a dose of 10 mg.

With daily dosages of 10 mg, a concentrated oral formulation with aconcentration of 20 mg of active ingredient per mL could be appropriate.A concentration of 20 mg per mL and a drop number of 20 drops/mL wouldmake it possible to administer 10 drops for a dose of 10 mg.

With daily dosages of 20 mg, a concentrated oral formulation with aconcentration of 20 mg of active ingredient per mL could be appropriate.A concentration of 20 mg per mL and a drop number of 20 drops/mL wouldmake it possible to administer 20 drops for a dose of 20 mg.

Accordingly, in one embodiment a concentrated oral formulations of thepresent invention comprise approximately 2.5-20 mg/mL of a salt of thepresent invention. Particular examples include approximately 5-20 mg/mL,approximately 5-15 mg/mL, approximately 5-10 mg/mL, and approximately2.5, 5, 7.5, 10, 15 or 20 mg/mL.

In one embodiment, a concentrated oral formulation of the presentinvention comprises at least 2.5 mg/mL of a salt of the presentinvention.

In one embodiment, a concentrated oral formulation of the presentinvention comprises at least 5 mg/mL of a salt of the present invention.

In one embodiment, a concentrated oral formulation of the presentcomprises at least 10 mg/mL of a salt of the present invention.

In one embodiment, a concentrated oral formulation of the presentcomprises at least 20 mg/mL of a salt of the present invention.

In addition to a salt of the present application, the oral formulationof the present application, and in particular the concentrated oralformulations may comprise solvents, buffers, surfactants, surfacetension modifiers, viscosity modifiers, preservatives, antioxidants,colorants, taste maskers, flavours etc.

Examples of solvents include water and other solvents, which aremiscible with water or solubilizing agents and suitable for oralpurposes. Examples of suitable solvents are ethanol, propylene glycol,glycerol, polyethylene glycols, poloxamers, sorbitol and benzyl alcohol.The aqueous solubility of the active ingredient may further be enhancedby the addition to the solution of a pharmaceutically acceptableco-solvent, a cyclodextrin or a derivative thereof.

A buffer system may be used to maintain the pH of the formulation in anoptimal pH-range. A buffer system is a mixture of appropriate amounts ofa weak acid such as acetic, phosphoric, succinic, tartaric, lactic orcitric acid and its conjugate base. Ideally, the buffer system hassufficient capacity to remain in the intended pH range upon dilutionwith a neutral, a slightly acidic or a slightly basic beverage.

Surfactants are substances, which solubilize active compounds, which areinsufficiently soluble in an aqueous medium, usually with the formationof micelles. Preferably, the surfactant used should be non-ionic due toless toxicity. High concentrations of surfactants may be used to allowfor dilution during administration without precipitation. Examples ofsurfactants include tweens, spans and mono- and diglycerides.

Surface tension modifiers may be included to adjust the drop number forthe concentrated oral formulations. An example of a surface tensionmodifier is ethanol, which decreases the surface tension and increasesthe drop number.

Viscosity modifiers may be included to adjust the drop velocity for aconcentrated oral formulation. The drop velocity for α formulation to bemeasured out in discrete drops from a container fitted with a dropaggregate should preferably not exceed 2 drops per second. Examples ofviscosity modifiers include ethanol, hydroxyethylcellulose,carboxymethylcellulose sodium, methylcellulose, polyvinyl alcohol,polyvinylpyrrolidone, polyethylene glycol and glycerine.

Preservative agents may be added to prevent the growth of microorganisms such as bacteria, yeasts and fungi in liquid formulations,which are likely to be used repeatedly. Suitable preservatives should bepharmaceutically acceptable, physicochemical stable and effective in thedesired pH range. Examples of preservative agents include ethanol,benzoic acid, sorbic acid, methylparaben, propylparaben and benzylalcohol.

A drug substance is typically more sensitive to chemical degradation indissolved than in solid form; hence it may be necessary to include anantioxidant in the liquid formulation. Examples of antioxidants includepropyl gallate, ascorbyl palmitate, ascorbic acid, sodium sulphite,citric acid and EDTA.

Colouring agents may be used in some formulations to introduce auniformity of appearance to the product. Some active ingredients mayfurther be very sensitive to light and it may prove necessary to addcolouring agents to the drop formulations to protect them from light andfor the purpose of stabilization. Suitable colouring agents include forexample tartrazine and sunset yellow.

Sweetening agents may mask unpleasant taste associated with someformulations or to achieve a desired taste. Examples of sweeteningagents are saccharin, sodium salt of saccharin, glucose, sorbitol,glycerol, acesulfame potassium and neohesperidin dihydrochalcon. Thetaste may be optimized further by the addition of one or more flavouringsubstances. Suitable flavouring substances are fruit flavours such ascherry, raspberry, black currant, lemon or strawberry flavour or otherflavours such as liquorish, anis, peppermint, caramel etc. Particularexamples of concentrated oral formulations of lactic acid addition saltsof Compound I, which may be administered with a drop aggregate, arelisted below. Further examples are provided in the Examples section. Byactive compound is meant the DL-lactate, the L-lactate or the D-lactatesalt of compound I. 1% of the free base form of compound I correspondsto 1.3% of the active compound. 2% of the free base form of compound Icorresponds to 2.6% of the active compound. The examples are merelyintended to illustrate the invention and should not be construed aslimiting

0.33% active compound

0.08% methylparahy droxy benzoate

0.02% propylparahy droxy benzoate

0.2% hydroxyethylcellulose

Water q.s. ad 100%

0.65% active compound

5% hydroxy propyl betacyclodextrin

0.02% propyl gallate

0.2% sorbinsyre

Water q.s. ad 100%

1.3% active compound

0.1% hydroxyethylcellulose

Water q.s. ad 100%

2.6% active compound

10% hydroxyl propyl betacyclodextrin

Water q.s. ad 100%

The pharmacological profile of compound I is disclosed in WO 03/029232,WO 2007/144005 and WO 2008/113359. In brief, compound I is an inhibitorof the serotonin transporter, an antagonist at the 5-HT₃ receptor and anagonist at the 5-HT_(1A) receptor. Compound I gives rise to an increasein the extracellular levels of serotonin, noradrenaline, dopamine andacetylcholine in rat brains [Moore et al, Eur. Neuropsychopharmacol.,18, suppl 4, s321, 2008]. The '359 application also discloses theresults from clinical trials in depressed patients with thecorresponding HBr addition salt which show a surprisingly low level ofsleep and sexually related adverse events.

On this background, salts of the present invention are expected to beuseful in the treatment of mood disorders, such as major depressivedisorder, generalised anxiety disorder, panic disorder, post traumaticstress disorder, and depression associated with anxiety, i.e.co-existing depression and anxiety. The impact on extracellularacetylcholine levels is expected to translate into an effect oncognition, cf. the use of acetylcholine esterase inhibitors in thetreatment of Alzheimer's disease. Thus, the salts of the presentinvention may also be used in the treatment of depression associatedwith cognitive impairment and Alzheimer's disease.

A fraction of patients with major depressive disorder will respond totreatment with e.g. a selective serotonin transport inhibitor in thesense that they will improve on clinically relevant scales, such as HAMDor MADRS, but where other symptoms, such as cognitive and/or sleepsymptoms remain. In the present context, these patients are referred toas suffering form depression with residual symptoms. The salts of thepresent invention are expected to be useful in the treatment of suchpatients.

Pre-clinical data presented e.g. in WO 2008/113359 supports the notionthat compound I may be used in the treatment of pain. In one embodiment,pain is or pain is associated with chronic pain including phantom limbpain, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia(PHN), carpal tunnel syndrome (CTS), HIV neuropathy, complex regionalpain syndrome (CPRS), trigeminus neuralgia, tic douloureux, surgicalintervention (e.g. post-operative analgesics), diabetic vasculopathy,capillary resistance, diabetic symptoms associated with insulitis, painassociated with menstruation, pain associated with cancer, dental pain,headache, migraine, tension-type headache, trigeminal neuralgia,temporomandibular joint syndrome, myofascial pain, muscular injury,fibromyalgia syndrome, bone and joint pain (osteoarthritis), rheumatoidarthritis, rheumatoid arthritis and edema resulting from traumaassociated with burns, strains or fracture bone pain due toosteoarthritis, osteoporosis, bone metastases or unknown reasons, gout,fibrositis, myofascial pain, thoracic outlet syndromes, upper back painor lower back pain (wherein the back pain results from systematic,regional, or primary spine disease (radiculopathy), pelvic pain, cardiacchest pain, non-cardiac chest pain, spinal cord injury (SCI)-associatedpain, central post-stroke pain, cancer neuropathy, AIDS pain, sicklecell pain or geriatric pain. In one embodiment, pain is irritable bowlsyndrome (IBS).

On the basis of the pharmacological profile, it is also expected thatthe salts of the present invention may be useful in the treatment ofeating disorders, such as obesity, binge eating, anorexia and bulimianervosa, and substance abuse, such as alcohol, nicotine and drug abuse.

Hence, in one embodiment, the invention relates to a method of treatinga disease selected from mood disorders; major depressive disorder;general anxiety disorder; panic disorder; post traumatic stressdisorder; depression associated with cognitive impairments, Alzheimer'sdisease or anxiety; depression with residual symptoms; chronic pain;eating disorder or abuse said method comprising the administration of atherapeutically effective amount of a liquid formulation of the presentinvention to a patient in need thereof.

Due to the very low level of adverse events observed in treatment with1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine, a liquid formulationof the present invention may also be useful as second line treatment forpatients who cannot use other drugs, such as other anti-depressants,such as selective serotonin reuptake inhibitors (SSRI), selectivenoradrenalin reuptake inhibitors (NRI), noradrenaline/serotonin reuptakeinhibitors (SNRI) or tri-cyclics (TCA) due to sleep or sexually relatedadverse events. In this embodiment, the patient to be treated hasreceived another medication (or is still receiving it), which medicationwas ceased or reduced (or has to be ceased or reduced) due to sleep orsexually related adverse events. In one embodiment, said liquidformulation is a concentrated oral formulation.

In one embodiment, the patient to be treated has been diagnosed with thedisease said patient is being treated for.

A typical oral dosage is in the range of from about 0.01 to about 5mg/kg body weight per day, preferably from about 0.01 to about 1 mg/kgbody weight per day, administered in one or more dosages such as 1 to 3dosages. The exact dosage will depend upon the frequency and mode ofadministration, the sex, age, weight and general condition of thesubject treated, the nature and severity of the condition treated andany concomitant diseases to be treated and other factors evident tothose skilled in the art.

A typical oral dosage for adults is in the range of 0.5-50 mg/day of asalt of the present invention, such as 1-10 mg/day. This may typicallybe achieved by the administration of 0.5-50 mg, such as 0.5, 1, 2.5, 5,10, 15, 20 25, 30 or 40 mg of a salt of the present invention once ortwice daily. In case of pediatric treatment, the dose may be reducedaccording to age and/or body weight.

A “therapeutically effective amount” of a compound as used herein meansan amount sufficient to cure, alleviate or partially arrest the clinicalmanifestations of a given disease and its complications in a therapeuticintervention comprising the administration of said compound. An amountadequate to accomplish this is defined as “therapeutically effectiveamount”. The term also includes amounts sufficient to cure, alleviate orpartially arrest the clinical manifestations of a given disease and itscomplications in a treatment comprising the administration of saidcompound. Effective amounts for each purpose will depend on the severityof the disease or injury as well as the weight and general state of thesubject. It will be understood that determining an appropriate dosagemay be achieved using routine experimentation, by constructing a matrixof values and testing different points in the matrix, which is allwithin the ordinary skills of a trained physician.

The term “treatment” and “treating” as used herein means the managementand care of a patient for the purpose of combating a condition, such asa disease or a disorder. The term is intended to include the fullspectrum of treatments for a given condition from which the patient issuffering, such as administration of the active compound to alleviatethe symptoms or complications, to delay the progression of the disease,disorder or condition, to alleviate or relief the symptoms andcomplications, and/or to cure or eliminate the disease, disorder orcondition as well as to prevent the condition, wherein prevention is tobe understood as the management and care of a patient for the purpose ofcombating the disease, condition, or disorder and includes theadministration of the active compounds to prevent the onset of thesymptoms or complications. Nonetheless, prophylactic (preventive) andtherapeutic (curative) treatment are two separate aspect of theinvention. The patient to be treated is preferably a mammal, inparticular a human being.

In one embodiment, the invention relates to the use of a salt of thepresent invention for the manufacture of a liquid formulation for thetreatment of a disease selected from mood disorders; major depressivedisorder; general anxiety disorder; panic disorder; post traumaticstress disorder; depression associated with cognitive deficits,Alzheimer's disease or anxiety; depression with residual symptoms;chronic pain; eating disorder or abuse.

In one embodiment, said salt is chosen from the β form of the DL-lactatesalt and the MH2 form of the L-lactate salt.

In one embodiment, said liquid formulation is a concentrated oralformulation.

In one embodiment, the present invention relates to a salt of thepresent invention for use in the treatment of a disease selected frommood disorders; major depressive disorder; general anxiety disorder;panic disorder; post traumatic stress disorder; depression associatedwith cognitive deficits, Alzheimer's disease or anxiety; depression withresidual symptoms; chronic pain; eating disorder or abuse, wherein saidsalt is in a liquid formulation.

In one embodiment, said salt is chosen from the DL-lactate salt and theL-lactate salt.

In one embodiment, said liquid formulation is a concentrated oralformulation.

In one embodiment the present invention relates to a liquid formulationcomprising a salt of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazineselected from the DL-lactic acid addition salt, the L-lactic acidaddition salt and/or the D-lactic acid addition salt. In particular,said liquid formulation is a concentrated oral formulation.

In one embodiment the present invention relates to a compound which isthe L-lactic acid addition salt of1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine. Particular mentionis made of the MH2 form.

In one embodiment the present invention relates to a compound which isthe L-lactic acid addition salt of1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine with XRPD reflectionsat approximately 5.33, 9.75, 10.10, 14.44 and 14.63 (° 2θ) e.g. with anXRPD pattern as depicted in FIG. 3.

In one embodiment the present invention relates to a compound which isthe D-lactic acid addition salt of1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.

In one embodiment the present invention relates to a compound which isthe β form of the DL-lactic acid addition salt with XRPD reflections atapproximately 6.01, 10.10, 10.32, 12.06, 12.84, 13.08, 13.58 (° 2θ),e.g. with a XRPD pattern as depicted in FIG. 5.

The salts of the present invention may be administered either alone orin combination with another therapeutically active compound, wherein thetwo compounds may be administered either simultaneously or sequentially.Examples of therapeutically active compounds which may advantageously becombined with salts of the present invention include sedatives orhypnotics, such as benzodiazepines; anticonvulsants, such aslamotrigine, valproic acid, topiramate, gabapentin, carbamazepine; moodstabilizers such as lithium; dopaminergic drugs, such as dopamineagonists and L-Dopa; drugs to treat ADHD, such as atomoxetine;psychostimulants, such as modafinil, ketamine, methylphenidate andamphetamine; other antidepressants, such as mirtazapine, mianserin andbuproprion; hormones, such as T3, estrogen, DHEA and testosterone;atypical antipsychotics, such as olanzapine and aripiprazole; typicalantipsychotics, such as haloperidol; drugs to treat Alzheimer'sdiseases, such as cholinesterase inhibitors and memantine, folate;S-Adenosyl-Methionine; immunmodulators, such as interferons; opiates,such as buprenorphins; angiotensin II receptor 1 antagonists (ATIantagonists); ACE inhibitors; statins; and alpha1 adrenergic antagonist,such as prazosin.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference in theirentirety and to the same extent as if each reference were individuallyand specifically indicated to be incorporated by reference and were setforth in its entirety herein (to the maximum extent permitted by law),regardless of any separately provided incorporation of particulardocuments made elsewhere herein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context. For example, the phrase “the compound”is to be understood as referring to various “compounds” of the inventionor particular described aspect, unless otherwise indicated.

Unless otherwise indicated, all exact values provided herein arerepresentative of corresponding approximate values (e.g., all exactexemplary values provided with respect to a particular factor ormeasurement can be considered to also provide a correspondingapproximate measurement, modified by “about,” where appropriate).

The description herein of any aspect or aspect of the invention usingterms such as “comprising”, “having,” “including,” or “containing” withreference to an element or elements is intended to provide support for asimilar aspect or aspect of the invention that “consists of”, “consistsessentially of”, or “substantially comprises” that particular element orelements, unless otherwise stated or clearly contradicted by context(e.g., a composition described herein as comprising a particular elementshould be understood as also describing a composition consisting of thatelement, unless otherwise stated or clearly contradicted by context).

EXAMPLES Analysis

X-Ray powder diffractograms (XRPD) were measured on a PANalytical X'PertPRO X-Ray Diffractometer using CuK_(α1) radiation. The samples weremeasured in reflection mode in the 2θ-range 5-40° C. using anX'celerator detector. Throughout this document, diffraction data areindicated ±0.1 (° 2θ).

Example 1. AH1 Form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]Piperazine, L-Lactate

1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine base (5.00 g) wasdissolved in ethyl acetate (50 mL) at 50° C. The solution was a littleturbid and was filtered through a paper filter. L-(+)-lactic acid (1.84g) was added to the solution and stirred at room temperature.Precipitation started and the suspension was stirred at room temperaturefor two hours and the product was isolated by filtration. The solid wasdried in the vacuum oven at 40° C. over night. It was not possible tomeasure the aqueous solubility of the AH1 as the substance transformsinto monohydrate when exposed to water.

Example 2. MH1 Form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]Piperazine, L-Lactate

100 mg of AH1 form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine, L-lactate from example 1 was left in an open container atambient conditions (22° C., 30% RH). It was not possible to measuresolubility of the MH1, as the compound transforms into the MH2 inaqueous slurry.

Example 3. MH2 Form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]Piperazine, L-Lactate

To 100 mg of MH1 form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine, L-lactate from example 2 was added 1 mL of water, and themixture was left overnight. The precipitate (MH2-form) is filtered of.

Example 4. α form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine, DL-Lactate

1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine base (5.00 g) wasdissolved in ethyl acetate (50 mL) at 50° C. The solution was a littleturbid and was filtered through a paper filter and became clear.DL-lactic acid (1.68 g) was added to the solution and stirred at roomtemperature. Precipitation started after two hours. The suspension wasstirred at room temperature for two hours and the product isolated byfiltration. The solid was dried in the vacuum oven at 40° C. over night.It was not possible to measure the solubility of the α form in water, asthe compound transformed into the β form in the aqueous slurry.

Example 5. β Form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]Piperazine, DL-Lactate

100 mg of α form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine, DL-lactate from example 5 was added 1 mL of water, and themixture is left overnight. The precipitate (β-form) was filtered of.

Example 6. MH Form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]Piperazine, DL-Lactate

10 mg of α form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine, DL-lactate from example 5 was exposed to high relativehumidity (25° C., 95% RH) for 4 h. It was not possible to measuresolubility of MH in water because it transformed into the beta form inaqueous slurry.

Example 7. γ Form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]Piperazine, DL-Lactate

10 mg of MH form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine, DL-lactate from example 7 was heated to 50° C. It was notpossible to measure aqueous solubility of the γ form because ittransforms into the beta form in aqueous slurry.

Example 8. β form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]Piperazine, DL-Lactate

200 g of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl] piperazine, HBr (526mmol) was stirred in Me-THF (3.5 L) and 1 M NaOH (1 L) were added. Thesuspension was stirred for 15 minutes after which all solids weredissolved. The phases were separated, and after blank filtration theMe-THF phase was reduced to half volume. After cooling to roomtemperature DL-lactic acid (1.5 eq˜789 mmol) was added and the solutionwas seeded with 0.5% of the J form. After 5 minutes, the precipitationstarts and the suspension was left stirring at ambient temperatureovernight. The suspension was then cooled on ice, filtered and washedwith 200 mL Me-THF and dried overnight under vacuum at 50° C.

TABLE 1 Summary of selected reflection for the XRPD patterns, meltingpoint and room temperature solubility of the forms of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl] piperazine, lactate MeltingCrystal Selected XRPD point Solubility Salt Form reflections (°2θ) (°C.) (mg base/mL) L-lactate AH1 4.65, 10.96, 13.97 ~140 Na L-lactate MH14.36, 8.73, 11.18, na na (>26)    11.81, 12.78, 13.11 L-lactate MH25.33, 9.75, 10.10, na  26 (pH = 5.2) 14.44, 14.63 DL-lactate α 6.67,8.33, 9.44, ~119 na 11.82, 15.35 DL-lactate β 6.01, 10.10, 10.32, ~149 8(pH = 6) 12.06, 12.84, 13.08, 13.58 DL-lactate MH 4.37, 8.73, 11.14, nana 11.78, 12.75, 13.11 DL-lactate γ 4.63, 10.94, 11.65, ~123 na 13.93 na= non applicable

TABLE 2 Room temperature solubility of previously known salt forms of1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl] piperazine Solubility Salt(mg base/mL) Crystalline base 0.1 HBr, α-form 2.0 HBr, β-form 1.2 HCl3.0 HCl, MH 2.0 Fumarate 0.4 Maleate ~1 Meso-tartrate ~0.7L-(+)-tartrate ~0.4 D-(−)-tartrate ~0.4 Sulphate ~0.1 Phosphate ~1Nitrate ~0.8 Mesylate >45

Example 9. Synthesis of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]Piperazine D,L-Lactate Salt

50 g (132 mmol) of the HBr salt was suspended in 800 mL toluene and 250mL (250 mmol; 1.9 eq) 1M aq. NaOH was added. The two-phase mixture waswarmed to 65° C. until all solid has gone into solution and then cooledto room temperature. The phases were separated, and the organic phasewas evaporated in vacuo to give a slightly yellow solid. 125 mL ethanoland 20 mL (269 mmol; 2.0 eq) DL-lactic acid (90%) were added, and thesuspension was warmed until all solids were dissolved, followed bycooling to room temperature. The solution was seeded with a few crystalsof 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine D,L-lactate βform, and the suspension was stirred over night at room temperature andsubsequently cooled with an ice-bath. The precipitate was filtered-offand washed with ethanol, dried in vacuum oven to give 36.5 g1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine D,L-lactate β form(71% yield).

Example 10. Concentrated Oral Formulations

The concentrated oral formulations indicated below were prepared andexposed to stability testing under conditions as indicated. 25/60indicates 25° C. and 60% RH, 40/75 indicates 40° C. and 75% RH, and 60indicates 60° C. The numbers indicate the amount of residual activecompound following the test period.

The residual amount of1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine in the oral dropformulations was determined by gradient reverse-phase HPLC. The mobilephase consisted of a mixture of water and acetonitrile with TFA added.Detection was by UV at 226 nm.

a)1.3% active compound˜1% free base0.08% methylparahydroxybenzoate0.02% propylparahydroxybenzoate

Water q.s. ad 100%

Time 25/60 40/75 60 (months:) mg/ml mg/ml mg/ml 0 10.6 10.6 10.6 ½ 10.610.4 10.4 1 10.4 10.5 10.4 2 10.1 10.1 10.2 3 9.8 9.8 9.9b)1.3% active compound˜1% free base5% hydroxy propyl betacyclodextrin

Water q.s. ad 100%

Time 25/60 40/75 60 (months:) mg/ml mg/ml mg/ml 0 10.4 10.4 10.4 ½ 10.310.3 10.3 1 10.4 10.4 10.4 2 9.9 10.1 10.2 3 9.7 9.5 9.8c)1.3% active compound˜1% free base0.1% hydroxyethylcellulose

Water q.s. ad 100%

Time 25/60 40/75 60 (months:) mg/ml mg/ml mg/ml 0 10.4 10.4 10.4 ½ 10.510.6 10.5 1 10.4 10.5 10.5 2 10.1 10.2 10.1 3 9.6 9.5 9.6d)1.3% active compound˜1% free base1.1% L-lactic acid0.1% hydroxyethylcellulose

Water q.s. ad 100%

Time 25/60 40/75 60 (months:) mg/ml mg/ml mg/ml 0 10.5 10.5 10.5 ½ 10.510.7 10.5 1 9.7 9.8 9.8 2 10.4 10.4 10.3 3 10.1 10.1 10.1 6 9.8 9.8 9.8e)2.6% active compound˜2% free base10% hydroxy propyl betacyclodextrin

Water q.s. ad 100%

Time 25/60 40/75 60 (months:) mg/ml mg/ml mg/ml 0 20.6 20.6 20.6 ½ 20.720.6 20.8 1 19.9 18.9 19.6 2 21.1 21.0 20.9 3 20.2 20.8 20.7 6 19.7 20.1f)2.6% active compound˜2% free base10% hydroxy propyl betacyclodextrin10% ethanol 96%

Water q.s. ad 100%

Time 25/60 40/75 60 (months:) mg/ml mg/ml mg/ml 0 20.8 20.8 20.8 ½ 20.920.7 21.1 1 19.7 19.8 19.7 2 21.0 20.9 20.8 3 20.7 20.6 20.9 6 19.9 20.0g)2.6% active compound˜2% free base10% methyl betacyclodextrin

Water q.s. ad 100%

Time 25/60 40/75 60 (months:) mg/ml mg/ml mg/ml 0 20.8 20.8 20.8 ½ 19.619.3 19.6 1 21.0 20.4 20.6 2 20.0 20.5 20.2 3 20.8 21.1 21.0 6 20.3 19.919.6h)2.6% active compound˜2% free base10% methyl betacyclodextrin10% ethanol 96%

Water q.s. ad 100%

Time 25/60 40/75 60 (months:) mg/ml mg/ml mg/ml 0 21.0 21.0 21.0 ½ 19.720.2 19.8 1 20.7 20.9 20.8 2 20.2 20.7 20.4 3 21.3 21.2 21.0 6 20.3 20.520.0

1. A liquid pharmaceutical formulation prepared from: a salt of1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine, the salt beingselected from the group consisting of the β form of a DL-lactic acidaddition salt, the MH2 form of a L-lactic acid addition salt and the MH2form of a D-lactic acid addition salt; and ethanol.
 2. The liquidformulation of claim 1, wherein the salt is the β form of the DL-lacticacid addition salt.
 3. The liquid formulation of claim 1, wherein thesalt is the MH2 form of the L-lactic acid addition salt.
 4. The liquidformulation of claim 1, wherein the salt is the MH2 form of the D-Lacticacid addition salt.
 5. The liquid formulation of claim 1, wherein theconcentration of the salt is at least 2.5 mg/mL.
 6. A container fittedwith a drop aggregate, which container comprises the liquid formulationof claim
 1. 7. The container of claim 6, wherein the salt is the β formof the DL-lactic acid addition salt.
 8. The container of claim 6,wherein the salt is the MH2 form of the L-lactic acid addition salt. 9.The container of claim 6, wherein the salt is the MH2 form of theD-Lactic acid addition salt.
 10. The container of claim 6, wherein theconcentration of the salt is at least 2.5 mg/mL.